An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.

2019 年冠状病毒病 (COVID-19) 的持续大流行现在是对全球公共卫生的最大威胁。草药及其衍生的天然产物在 COVID-19 的治疗中备受关注，但尚未阐明天然产物抑制 SARS-CoV-2 的详细机制。在这里，我们展示了桔梗 D (PD)，一种在桔梗中含量丰富的三萜皂苷(PG) 是东亚常用的一种饮食和药用草药，可通过溶酶体和跨膜蛋白酶丝氨酸 2 (TMPRSS2) 驱动的进入有效阻断 SARS-CoV-2 的两种主要感染途径。从机制上讲，PD 通过重新分配膜胆固醇以防止膜融合来阻止 SARS-CoV-2 进入宿主，这可以通过 PD 包封剂处理来恢复。此外，PD 的抑制作用通过NPC1的药理学抑制或基因沉默得到概括。，它在尼曼-匹克 C 型 (NPC) 患者中发生突变，表现出膜胆固醇分布紊乱。最后，现成的当地食品或含有 PG 根的草药对 SARS-CoV-2 感染显示出类似的抑制作用。我们的研究表明，PD 是一种有效的天然产物，可用于预防或治疗 COVID-19，而短暂破坏膜胆固醇的分布是 SARS-CoV-2 感染的一种潜在的新型治疗策略。